The present invention relates to a novel 3-phenyl-2-pyrazoline derivative or 3-phenyl-tetrahydropyridazine derivative, as well as to a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to an agent containing the above compound, which can activate glutamic acid transporter and is useful for treatment and/or prevention of cerebral ischemia (cerebral infarct and brain edema), cephalotrauma, glaucoma, retinopathy, epilepsy and amyotrophic lateral sclerosis (ALS), all caused by glutamic acid toxicity.
Glutamic acid is an important excitatory neurotransmitter in the central nervous system and has a close connection with neuropathy caused during cerebral ischemia. There are reports on the excessive effusion of glutamic acid caused by ischemia in test animals, and also on persistent effusion of large amount of glutamic acid in the brain tissue of cerebral ischemia patient [B. Meldrum: Trends. Pharmacol. Sci. 1990, 11, 379-387]. Therefore, it is expected that brain tissue can be protected from cell death by controlling the excessive effusion of glutamic acid caused during ischemia.
Glutamic acid which effuses excessively into synapse gaps, is taken into cells by the action of glutamic acid transporter present in neurocytes or astrocytes, whereby an equilibrium is maintained. Up to now, five kinds of sodium-dependent glutamic acid transporters (GLT-1, GLAST, EAACI, EAAT4 and EAAT5) have been cloned, and an active study has been made in recent years in order to make clear the functions thereof. It is considered that glutamic acid transporter is activated with an increase in the ectocytic concentration of glutamic acid, caused during ischemia and has an important role in protecting neurocytes from glutamic acid toxicity. Also, there is a report that the degeneration of glutamic acid transporter has a connection with neurodegeneration such as amyotrophic lateral sclerosis (ALS). Therefore, by activating glutamic acid transporter and removing the glutamic acid excessively effusing into synapse gaps, protective effects can be expected for various diseases considered to be caused by glutamic acid toxicity, such as cerebral ischemia (cerebral infarct and brain edema), sequela of cerebral ischemia, cephalotrauma, glaucoma, retinopathy, epilepsy, amyotrophic lateral sclerosis (ALS) and the like. However, there has heretofore been no report on any drug capable of activating glutamic acid transporter.